Amphotericin B (AMB) is an effective antifungal agent, and at present, is the drug of choice for most serious systemic fungal infections (reference 1). The drug is presently available for human use as a lyophilized powder of AMB and deoxycholate ("Fungizone"). The drug binds strongly to ergosterol, a major sterol component of fungal membranes, forming pores in the membranes which allow leakage of solute molecules. The drug also has a strong binding affinity for cholesterol, a sterol present in most mammalian cell membranes, and is therefore capable of disrupting host cells.
When AMB is administered in free form (i.e., as a reconstituted AMB/deoxycholate complex) side effects resulting from red blood cell disruption are observed initially, followed by more serious cardiotoxicity, CNS and bone-marrow effects. Renal toxicity, resulting from the body's attempt to clear the drug, is also present.
Several studies have shown that AMB toxicity can be reduced by administering the drug in a liposome-bound form (references 2-12). Typically, the LD.sub.50 of the drug increases from about 2-3 mg/kg body weight for the free drug up to about 8-15 mg/kg when the drug is administered in liposomal form. One limitation of liposomal formulations, however, is the apparent size instability of amphotericin B/liposomal particles when stored in an aqueous medium. Typically, AMB-containing liposomes which have an initial size distribution between about 200-300 nm will spontaneously form large liposomal structures of up to several microns on long-term storage in an aqueous medium. Liposomes with sizes greater than about 1-2 microns are generally more toxic than smaller liposomes when administered parenterally, i.e., into the bloodstream. The toxicity of large liposomes in the bloodstream is related in part to liposome blockage of the alveolar capillaries. There are also indications that relatively large liposomes are more toxic to the liver, presumably due to liposome accumulation in reticuloendothelial cells. Co-owned U.S. patent application for "Amphotericin B Liposome Composition", Ser. No. 781,395, filed Sept. 27, 1985, discloses a novel method of preparing and storing AMB liposomes which largely overcome the size-growth problem mentioned above.
An amphotericin B composition formed by complexing AMB with a polyethylene derivative of cholesterol (PEG-cholesterol) has also been proposed (PCT application US84/00855). The formulation increased the LD.sub.50 of AMB to 10.0 mg/kg in mice, from 3.8 mg/kg for Fungizone, and was also less cytotoxic in cell culture. It is not known how and whether AMB complexing to PEG-cholesterol affects therapeutic efficacy against fungal infection in vivo, not whether the complex can be stored in a size-stable form.